tbuckley/cabot-search huggingface dataset:
Association of Adherence to Healthy Lifestyle Recommendations With All-Cause and Cause-Specific Mortality Among Former Smokers
Authors: Maki Inoue-Choi, Yesenia Ramirez, Ami Fukunaga, Charles E. Matthews, Neal D. Freedman
Journal: JAMA Network Open (2022)

Importance The benefits of smoking cessation are well known, but former smokers have a higher health risk than never smokers. The impact of former smokers’ engaging in other aspects of a healthy lifestyle is unclear. Objective To assess the association between adherence to evidence-based lifestyle recommendations and mortality among former smokers. Design, Setting, and Participants This prospective cohort study included 159 937 participants in the National Institutes of Health–AARP Diet and Health Study of older US adults who completed the baseline and risk factor questionnaires and self-identified as former smokers. Baseline questionnaires were mailed from 1995 to 1996. Data analysis was performed from November 2020 to November 2021. Exposures Adherence to evidence-based lifestyle recommendations was scored for body weight (scores, 0-2), diet (scores, 0-3), physical activity (scores, 0-2), and alcohol intake (scores, 0-1) recommendations, with higher scores indicating better adherence. Individual lifestyle adherence scores were summed to make a total adherence score (scores, 0-8). Main Outcomes and Measures The primary outcomes were all-cause and cause-specific mortality through December 31, 2019, with a mean (SD) follow-up of 18.9 (6.3) years. Hazard ratios (HRs) and 95% CIs were computed using a multivariable Cox proportional hazards regression model. Results Among 159 937 former smokers (mean [SD] age, 62.6 [5.2] years; 106 912 [66.9%] male; 149 742 [93.6%] White), 86 127 deaths occurred. A higher total adherence score was associated with lower all-cause mortality (HR per unit increase, 0.95; 95% CI, 0.94-0.95). Compared with the lowest total adherence score category (scores, 0-2), the HRs for all-cause mortality were 0.88 (95% CI, 0.86-0.90) for scores of 3 to 4, 0.80 (95% CI, 0.79-0.82) for scores of 5 to 6, and 0.73 (95% CI, 0.71-0.75) for scores of 7 to 8. Associations were observed regardless of health status, comorbid conditions, the number of cigarettes participants used to smoke per day, years since cessation, and age at smoking initiation. When examined individually, the HRs for highest vs lowest adherence score were 0.86 (95% CI, 0.84-0.88) for body weight, 0.91 (95% CI, 0.90-0.93) for diet, 0.83 (95% CI, 0.81-0.85) for physical activity, and 0.96 (95% CI, 0.94-0.97) for alcohol intake recommendations. Participants with a higher total adherence score also had a lower risk of mortality from cancer, cardiovascular disease, and respiratory disease. Conclusions and Relevance In a large US cohort of former smokers, better adherence to healthy lifestyle recommendations was associated with lower mortality risk. These results provide evidence that former smokers may benefit from adhering to lifestyle recommendations, as do other groups.
Imaging cellular immunotherapies and immune cell biomarkers: from preclinical studies to patients
Authors: Alessia Volpe, Prasad S Adusumilli, Heiko Schöder, Vladimir Ponomarev
Journal: Journal for ImmunoTherapy of Cancer (2022)

Cellular immunotherapies have emerged as a successful therapeutic approach to fight a wide range of human diseases, including cancer. However, responses are limited to few patients and tumor types. An in-depth understanding of the complexity and dynamics of cellular immunotherapeutics, including what is behind their success and failure in a patient, the role of other immune cell types and molecular biomarkers in determining a response, is now paramount. As the cellular immunotherapy arsenal expands, whole-body non-invasive molecular imaging can shed a light on their in vivo fate and contribute to the reliable assessment of treatment outcome and prediction of therapeutic response. In this review, we outline the non-invasive strategies that can be tailored toward the molecular imaging of cellular immunotherapies and immune-related components, with a focus on those that have been extensively tested preclinically and are currently under clinical development or have already entered the clinical trial phase. We also provide a critical appraisal on the current role and consolidation of molecular imaging into clinical practice.
Mesenchymal cell replacement corrects thymic hypoplasia in murine models of 22q11.2 deletion syndrome
Authors: Pratibha Bhalla, Qiumei Du, Ashwani Kumar, Chao Xing, Angela Moses, Igor Dozmorov, Christian A. Wysocki, Ondine B. Cleaver, Timothy J. Pirolli, Mary Louise Markert, Maria Teresa de la Morena, Antonio Baldini, Nicolai S.C. van Oers
Journal: Journal of Clinical Investigation (2022)

22q11.2 deletion syndrome (22q11.2DS) is the most common human chromosomal microdeletion, causing developmentally linked congenital malformations, thymic hypoplasia, hypoparathyroidism, and/or cardiac defects. Thymic hypoplasia leads to T cell lymphopenia, which most often results in mild SCID. Despite decades of research, the molecular underpinnings leading to thymic hypoplasia in 22q11.2DS remain unknown. Comparison of embryonic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) revealed proportions of mesenchymal, epithelial, and hematopoietic cell types similar to those of control thymuses. Yet, the small thymuses were growth restricted in fetal organ cultures. Replacement of Tbx1neo2/neo2 thymic mesenchymal cells with normal ones restored tissue growth. Comparative single-cell RNA-Seq of embryonic thymuses uncovered 17 distinct cell subsets, with transcriptome differences predominant in the 5 mesenchymal subsets from the Tbx1neo2/neo2 cell line. The transcripts affected included those for extracellular matrix proteins, consistent with the increased collagen deposition we observed in the small thymuses. Attenuating collagen cross-links with minoxidil restored thymic tissue expansion for hypoplastic lobes. In colony-forming assays, the Tbx1neo2/neo2-derived mesenchymal cells had reduced expansion potential, in contrast to the normal growth of thymic epithelial cells. These findings suggest that mesenchymal cells were causal to the small embryonic thymuses in the 22q11.2DS mouse models, which was correctable by substitution with normal mesenchyme.
Association of Follow-up Blood Cultures With Mortality in Patients With Gram-Negative Bloodstream Infections
Authors: Joshua T. Thaden, Sarah Cantrell, Michael Dagher, Yazhong Tao, Felicia Ruffin, Stacey A. Maskarinec, Stacy Goins, Matthew Sinclair, Joshua B. Parsons, Emily Eichenberger, Vance G. Fowler
Journal: JAMA Network Open (2022)

Importance Obtaining follow-up blood cultures (FUBCs) in patients with Staphylococcus aureus bloodstream infection (BSI) is standard practice, although its utility in patients with gram-negative bacterial BSI (GN-BSI) is unclear. Objective To examine whether obtaining FUBCs is associated with decreased mortality (key question [KQ] 1) and whether positive vs negative FUBCs are associated with increased mortality (KQ2). Data Sources MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and gray literature were searched from inception to March 11, 2022. Study Selection Two investigators used predefined eligibility criteria to independently screen titles, abstracts, and relevant full texts. Randomized clinical trials or observational studies that matched or statistically adjusted for differences in, at minimum, level of acute illness between patients in the intervention (eg, FUBCs obtained) and control (eg, FUBCs not obtained) groups were included in primary analyses. Articles published in languages other than English were excluded. Data Extraction and Synthesis Data abstraction and quality assessments were performed by one investigator and verified by a second investigator. Risk of bias was assessed with the Newcastle-Ottawa Scale. Effect sizes were pooled using random-effects models. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcomes and Measures Mortality before hospital discharge or up to 30 days from the index blood culture. Results From 3495 studies, 15 were included (all nonrandomized). In the 5 studies (n = 4378 patients) that met criteria for the KQ1 primary analysis, obtaining FUBCs was associated with decreased mortality (hazard ratio, 0.56; 95% CI, 0.45-0.71). For KQ2, 2 studies met criteria for the primary analysis (ie, matched or statistically adjusted for differences in patients with positive vs negative FUBCs), so an exploratory meta-analysis of all 9 studies that investigated KQ2 (n = 3243 patients) was performed. Positive FUBCs were associated with increased mortality relative to negative blood cultures (odds ratio, 2.27; 95% CI, 1.54-3.34). Limitations of the literature included a lack of randomized studies and few patient subgroup analyses. Conclusions and Relevance In this systematic review and meta-analysis, obtaining FUBCs in patients with GN-BSI was associated with decreased mortality. The benefit of FUBCs may stem from identification of patients with positive FUBCs, which was a poor prognostic marker.
Comparison of Sodium-Glucose Cotransporter 2 Inhibitors vs Glucagonlike Peptide-1 Receptor Agonists and Incidence of Dry Eye Disease in Patients With Type 2 Diabetes in Taiwan
Authors: Yu-Chen Su, Jia-Horung Hung, Kai-Cheng Chang, Chi-Chin Sun, Yi-Hsun Huang, Chaw-Ning Lee, Ming-Jui Hung, Chi-Chun Lai, Shih-Chieh Shao, Edward Chia-Cheng Lai
Journal: JAMA Network Open (2022)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to improve low-grade systemic and tissue inflammation; however, the association between SGLT2 inhibitor use and the incidence of dry eye disease (DED) has not been explored.To investigate the association between SGLT2 inhibitor use and dry eye disease in patients with type 2 diabetes (T2D).A retrospective cohort analysis of the largest multi-institutional electronic medical records database in Taiwan was conducted to identify patients with T2D newly receiving SGLT2 inhibitors or glucagonlike peptide-1 receptor agonists (GLP-1 RAs) from 2016 to 2018. Data analysis was performed from March 1 to May 31, 2022. Propensity scores with inverse probability of treatment weighting were generated to enable homogeneous comparisons between the 2 groups.Treatment with SGLT2 inhibitors or GLP-1 RAs.Incident dry eye disease, which was defined by clinical diagnoses, plus the related drug prescription. Cox proportional hazards regression models were used to estimate hazard ratios with 95% CIs for the risk of DED.A total of 10 038 and 1077 T2D patients newly receiving SGLT2 inhibitors (mean [SD] age, 59.5 [12.1] years; 5689 [56.7%] men) or GLP-1 RAs (mean [SD] age, 58.5 [41.2] years; 587 [54.5%] men), respectively, were included in the analysis. The incidence of DED was lower in patients newly receiving SGLT2 inhibitors (9.0 events per 1000 person-years) compared with those receiving GLP-1 RAs (11.5 events per 1000 person-years), yielding a hazard ratio of 0.78 (95% CI, 0.68-0.89). Subgroup analyses indicated that the lowered DED risks associated with SGLT2 inhibitors in patients with T2D were similar across different age, sex, blood glucose level, and kidney function groups. Results from the sensitivity analyses (including the propensity score-matching approach, on-treatment analyses, and different follow-up periods of 1, 2, and 3 years) were similar to the main analyses.The findings of this study suggest that patients with T2D newly receiving SGLT2 inhibitors may have a lower risk for DED compared with those receiving GLP-1 RAs. Prospective studies are needed to analyze these results.
Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis
Authors: Weiqing Wang, Yi Xu, Lun Wang, Zhenzhen Zhu, Surita Aodeng, Hui Chen, Menghua Cai, Zhihao Huang, Jinbo Han, Lei Wang, Yuxi Lin, Yu Hu, Liangrui Zhou, Xiaowei Wang, Yang Zha, Weihong Jiang, Zhiqiang Gao, Wei He, Wei Lv, Jianmin Zhang
Journal: Nature Immunology (2022)
Training Deep Learning Models to Work on Multiple Devices by Cross-Domain Learning with No Additional Annotations
Authors: Yue Wu, Abraham Olvera-Barrios, Ryan Yanagihara, Timothy-Paul H. Kung, Randy Lu, Irene Leung, Amit V. Mishra, Hanan Nussinovitch, Gabriela Grimaldi, Marian Blazes, Cecilia S. Lee, Catherine Egan, Adnan Tufail, Aaron Y. Lee
Journal: Ophthalmology (2022)
A primary hierarchically organized patient-derived model enables in depth interrogation of stemness driven by the coding and non-coding genome
Authors: Héléna Boutzen, Seyed Ali Madani Tonekaboni, Michelle Chan-Seng-Yue, Alex Murison, Naoya Takayama, Nathan Mbong, Elvin Wagenblast, Elias Orouji, Andrea Arruda, Amanda Mitchell, Faiyaz Notta, Mark D. Minden, Mathieu Lupien, Kerstin B. Kaufmann, John E. Dick
Journal: Leukemia (2022)

Abstract Many cancers are organized as cellular hierarchies sustained by cancer stem cells (CSC), whose eradication is crucial for achieving long-term remission. Difficulties to isolate and undertake in vitro and in vivo experimental studies of rare CSC under conditions that preserve their original properties currently constitute a bottleneck for identifying molecular mechanisms involving coding and non-coding genomic regions that govern stemness. We focussed on acute myeloid leukemia (AML) as a paradigm of the CSC model and developed a patient-derived system termed OCI-AML22 that recapitulates the cellular hierarchy driven by leukemia stem cells (LSC). Through classical flow sorting and functional analyses, we established that a single phenotypic population is highly enriched for LSC. The LSC fraction can be easily isolated and serially expanded in culture or in xenografts while faithfully recapitulating functional, transcriptional and epigenetic features of primary LSCs. A novel non-coding regulatory element was identified with a new computational approach using functionally validated primary AML LSC fractions and its role in LSC stemness validated through efficient CRISPR editing using methods optimized for OCI-AML22 LSC. Collectively, OCI-AML22 constitutes a valuable resource to uncover mechanisms governing CSC driven malignancies.
Memory CD8+ T cell diversity and B cell responses correlate with protection against SARS-CoV-2 following mRNA vaccination
Authors: Nadia Brasu, Ines Elia, Valentina Russo, Gaia Montacchiesi, Simona Aversano Stabile, Carlo De Intinis, Francesco Fesi, Katiuscia Gizzi, Marco Macagno, Monica Montone, Benedetta Mussolin, Alba Grifoni, Silvia Faravelli, Silvia Marchese, Federico Forneris, Raffaele De Francesco, Alessandro Sette, Vincenzo Barnaba, Antonino Sottile, Anna Sapino, Luigia Pace
Journal: Nature Immunology (2022)
Adoption of Extended-Interval Dosing of Single-Agent Pembrolizumab and Comparative Effectiveness vs Standard Dosing in Time-to-Treatment Discontinuation
Authors: Garth W. Strohbehn, Robert Holleman, Jennifer Burns, Mandi L. Klamerus, Michael J. Kelley, Eve A. Kerr, Nithya Ramnath, Timothy P. Hofer
Journal: JAMA Oncology (2022)

Extended-interval dosing of pembrolizumab (400 mg every 6 weeks) was approved by US Food and Drug Administration (FDA) in April 2020 as an alternative to standard-interval dosing (200 mg every 3 weeks). Extended-interval dosing may enhance access, alleviate patient and health system financial toxicity, and improve patient quality of life, particularly during the COVID-19 pandemic. Neither adoption nor effectiveness of extended interval in the US has been adequately described.To describe adoption of extended-interval dosing of pembrolizumab since its FDA approval and to measure its preliminary real-world effectiveness compared with standard-interval dosing.This was a retrospective cohort study that used data from the Veterans Health Administration (VHA), a US-based, nationwide single-payer health system. Participants were veterans who were prescribed single-agent pembrolizumab within the VHA between April 1, 2020, and July 1, 2021. Patients receiving combinations of pembrolizumab and cytotoxic chemotherapy or tyrosine kinase inhibitors were excluded. A subcohort of veterans with non-small cell lung cancer (NSCLC) was also identified using claims-based codes.Single-agent pembrolizumab at extended or standard intervals.The number and proportion of single-agent pembrolizumab prescriptions that were extended compared with standard interval. Effectiveness was described in terms of time-to-treatment discontinuation (TTD) and extended- to standard-interval pembrolizumab prescriptions were compared using Cox proportional hazards regression.A total of 835 veterans (mean age [SD], 70.9 [8.7] years; 809 [96.9%] men) began single-agent pembrolizumab during the study period (all-diseases cohort), and of these, 234 (mean [SD] age, 71.6 [7.3] years; 225 [96.2%] men) had NSCLC (NSCLC cohort). Extended-interval adoption reached its steady state plateau of approximately 35% by January 2021; 65% of participants who began standard-interval single-agent pembrolizumab received only standard-interval dosing during the treatment course. In analysis consistent with the intention-to-treat principle, no differences in TTD were observed between standard- and extended-interval dosing in either the all-diseases cohort (HR, 1.00; 95% CI, 1.00-1.00) or the NSCLC cohort (HR, 1.00; 95% CI, 1.00-1.00).This retrospective cohort study found that extended-interval dosing comprised a minority of single-agent pembrolizumab prescriptions despite the FDA approval and its potential health system and public health benefits. The findings support the TTD equivalence of standard- and extended-interval pembrolizumab across indications, complementing clinical pharmacology and single-arm clinical trial data in melanoma. This study provides further support for extended-interval pembrolizumab dosing.
Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes
Authors: Satyaki Sengupta, Sanjukta Das, Angela C. Crespo, Annelisa M. Cornel, Anand G. Patel, Navin R. Mahadevan, Marco Campisi, Alaa K. Ali, Bandana Sharma, Jared H. Rowe, Hao Huang, David N. Debruyne, Esther D. Cerda, Malgorzata Krajewska, Ruben Dries, Minyue Chen, Shupei Zhang, Luigi Soriano, Malkiel A. Cohen, Rogier Versteeg, Rudolf Jaenisch, Stefani Spranger, Rizwan Romee, Brian C. Miller, David A. Barbie, Stefan Nierkens, Michael A. Dyer, Judy Lieberman, Rani E. George
Journal: Nature Cancer (2022)
Association of Sinoatrial Node Radiation Dose With Atrial Fibrillation and Mortality in Patients With Lung Cancer
Authors: Kyung Hwan Kim, Jaewon Oh, Gowoon Yang, Joongyo Lee, Jihun Kim, Seo-yeon Gwak, Iksung Cho, Seung Hyun Lee, Hwa Kyung Byun, Hyo-Kyoung Choi, Jinsung Kim, Jee Suk Chang, Seok-Min Kang, Hong In Yoon
Journal: JAMA Oncology (2022)

Importance Atrial fibrillation (AF) can develop following thoracic irradiation. However, the critical cardiac substructure responsible for AF has not been properly studied. Objective To describe the incidence of AF in patients with lung cancer and determine predictive cardiac dosimetric parameters. Design, Setting, and Participants This retrospective cohort study was performed at a single referral center and included 239 patients diagnosed with limited-stage small cell lung cancer (SCLC) and 321 patients diagnosed with locally advanced non–small cell lung cancer (NSCLC) between August 2008 and December 2019 who were treated with definitive chemoradiotherapy. Exposures Radiation dose exposure to cardiac substructures, including the chambers, coronary arteries, and cardiac conduction nodes, were calculated for each patient. Main Outcomes and Measures Main outcomes were AF and overall survival. Results Of the 239 and 321 patients with SCLC and NSCLC, the median (IQR) age was 68 (60-73) years and 67 (61-75) years, and 207 (86.6%) and 261 (81.3%) were men, respectively. At a median (IQR) follow-up time of 32.7 (22.1-56.6) months, 9 and 17 patients experienced new-onset AF in the SCLC and NSCLC cohorts, respectively. The maximum dose delivered to the sinoatrial node (SAN D max ) exhibited the highest predictive value for prediction of AF. A higher SAN D max significantly predicted an increased risk of AF in patients with SCLC (adjusted hazard ratio [aHR], 14.91; 95% CI, 4.00-55.56; P &amp;amp;lt; .001) and NSCLC (aHR, 15.67; 95% CI, 2.08-118.20; P = .008). However, SAN D max was not associated with non-AF cardiac events. Increased SAN D max was significantly associated with poor overall survival in patients with SCLC (aHR, 2.68; 95% CI, 1.53-4.71; P &amp;amp;lt; .001) and NSCLC (aHR, 1.97; 95% CI, 1.45-2.68; P &amp;amp;lt; .001). Conclusions and Relevance In this cohort study, results suggest that incidental irradiation of the SAN during chemoradiotherapy may be associated with the development of AF and increased mortality. This supports the need to minimize radiation dose exposure to the SAN during radiotherapy planning and to consider close follow-up for the early detection of AF in patients receiving thoracic irradiation.
Genetic footprints of assortative mating in the Japanese population
Authors: Kenichi Yamamoto, Kyuto Sonehara, Shinichi Namba, Takahiro Konuma, Hironori Masuko, Satoru Miyawaki, Yoichiro Kamatani, Nobuyuki Hizawa, Keiichi Ozono, Loic Yengo, Yukinori Okada
Journal: Nature Human Behaviour (2022)

Abstract Assortative mating (AM) is a pattern characterized by phenotypic similarities between mating partners. Detecting the evidence of AM has been challenging due to the lack of large-scale datasets that include phenotypic data on both partners, especially in populations of non-European ancestries. Gametic phase disequilibrium between trait-associated alleles is a signature of parental AM on a polygenic trait, which can be detected even without partner data. Here, using polygenic scores for 81 traits in the Japanese population using BioBank Japan Project genome-wide association studies data ( n = 172,270), we found evidence of AM on the liability to type 2 diabetes and coronary artery disease, as well as on dietary habits. In cross-population comparison using United Kingdom Biobank data ( n = 337,139) we found shared but heterogeneous impacts of AM between populations.